ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in other sections of the labeling:oHypersensitivity Reactions [see Warnings and Precautions (5.1)]oPancreatic Toxicity [see Warnings and Precautions (5.2)]oThrombosis [see Warnings and Precautions (5.3)]oHemorrhage [see Warnings and Precautions (5.4)]oHepatotoxicity [see Warnings and Precautions (5.5)]. oHypersensitivity Reactions [see Warnings and Precautions (5.1)]. oPancreatic Toxicity [see Warnings and Precautions (5.2)]. oThrombosis [see Warnings and Precautions (5.3)]. oHemorrhage [see Warnings and Precautions (5.4)]. oHepatotoxicity [see Warnings and Precautions (5.5)]. Most common adverse reactions (incidence 20%) are abnormal liver test, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensitivity, febrile neutropenia, decreased appetite, stomatitis, bleeding, and hyperglycemia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals Ireland Limited at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of RYLAZE described in the WARNINGS AND PRECAUTIONS reflect exposure to RYLAZE at various dosages, including dosages other than the recommended, used in combination with chemotherapy in 102 patients in JZP458-201 [see Clinical Studies (14)]. These patients received median of courses of RYLAZE (range: 1-14 courses); 38% of patients received at least four courses.The safety of RYLAZE described below was evaluated in cohort of 33 patients from JZP458-201 who received RYLAZE 25 mg/m2 intramuscularly on Monday, Wednesday, and Friday for doses as replacement for single dose of pegaspargase as component of multi-agent chemotherapy [see Clinical Studies (14)]. The patients had median age of 11 years (range: to 24 years); the majority of patients were male (51%) and white (73%). The patients received median of courses of RYLAZE (range: 1-14 cycles); 48% of patients received at least four courses.A fatal adverse reaction (infection) occurred in patient treated with the RYLAZE 25 mg/m2 dosage. Serious adverse reactions occurred in 55% of patients who received the RYLAZE 25 mg/m2 dosage. The most frequent serious adverse reactions (in >= 5% of patients) were febrile neutropenia, dehydration, pyrexia, stomatitis, diarrhea, drug hypersensitivity, infection, nausea, and viral infection. Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received the RYLAZE 25 mg/m2 dosage. Adverse reactions resulting in permanent discontinuation included hypersensitivity (6%) and infection (3%).All patients treated with the RYLAZE 25 mg/m2 dosage as component of multi-agent chemotherapy developed neutropenia, anemia, or thrombocytopenia. The most common nonhematological adverse reactions in patients were abnormal liver test, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensitivity, febrile neutropenia, decreased appetite, stomatitis, bleeding, and hyperglycemia. Table shows the common adverse reactions occurring in at least 15% of the patients.Table 2: Adverse Reactions (>= 15% incidence) in Patients Receiving RYLAZE 25 mg/m2 as Component of Multi-Agent Chemotherapy in Study JZP458-201Adverse ReactionRYLAZE 25 mg/m2 Dosagea N=33All Grades(%)Grades 3-4(%)Abnormal liver test7012Nausea469Musculoskeletal pain396Fatigue363Infectionb 3012Headache300Pyrexia276Drug hypersensitivity246Febrile neutropenia2424Decreased appetite216Stomatitis219Bleeding210Hyperglycemia213Abdominal pain180Tachycardia180Diarrhea186Constipation150Dehydration159Neuropathy peripheral150Cough150Insomnia150Includes grouped termsGrading is based on Common Terminology Criteria for Adverse Events version 5.0 RYLAZE was administered as component of multi-agent chemotherapy regimens. Does not include the following fatal adverse reactions: infection (N=1).Safety data for patients treated on Monday, Wednesday, and Friday schedule. Clinically relevant adverse reactions in 15% of patients who received RYLAZE in combination with chemotherapy included:Gastrointestinal disorders: Abdominal discomfort, abdominal distension, pancreatitisGeneral disorders and administration site conditions: Infusion site reaction, painInfections and infestations: Viral infection, bacterial infection, fungal infectionInvestigations: Blood fibrinogen decreased, activated partial thromboplastin time prolongedMetabolism and nutrition disorders: AcidosisMusculoskeletal and connective tissue disorders: Bone pain, muscular weakness, muscle spasmsNervous system disorders: ParesthesiaPsychiatric disorders: Agitation, anxiety, irritabilityRenal and urinary disorders: Acute kidney injurySkin and subcutaneous disorders: PruritusVascular disorders: Hypotension. 6.2 Immunogenicity The incidence of ADA and subsequent effects on pharmacokinetics, pharmacodynamics, safety, or effectiveness have not been established.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Asparaginase erwinia chrysanthemi (recombinant)-rywn is an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The pharmacological effect of RYLAZE is based on the killing of leukemic cells due to depletion of plasma asparagine. Leukemic cells with low expression of asparagine synthetase have reduced ability to synthesize asparagine, and therefore depend on an exogenous source of asparagine for survival.. 12.2 Pharmacodynamics Asparaginase erwinia chrysanthemi (recombinant)-rywn exposure-response relationships and the time course of pharmacodynamic response are unknown.. 12.3 Pharmacokinetics The pharmacokinetic parameters of asparaginase erwinia chrysanthemi (recombinant)-rywn are presented based on serum asparaginase activity (SAA) following administration of the approved recommended dosage in pediatric and young adult patients (1 to 24 years), unless otherwise specified. The exposures for asparaginase erwinia chrysanthemi (recombinant)-rywn are summarized in Table 3. Asparaginase erwinia chrysanthemi (recombinant)-rywn maximum SAA (Cmax) and area under the SAA-time curve (AUC) increase proportionally over dosage range from 12.5 to 50 mg/m2 (0.5 to times the approved recommended dose of 25 mg/m2).Table 3: RYLAZE Pharmacokinetic Parameters Based on SAAParameterDose in CourseGeometric Mean (%CV)Cmax (U/mL)11.80 (40%)72.24 (42%)C48h (U/mL)10.33 (88%)70.40 (93%)AUC0-48h (h.U/mL)137.9 (39%)748.5 (41%)a SAA 48 hours after the most recent dose AbsorptionThe median tmax of asparaginase erwinia chrysanthemi (recombinant)-rywn is 10 hours. The mean absolute bioavailability for IM administration is 37% in healthy subjects.DistributionThe geometric mean (%CV) apparent volume of distribution of asparaginase erwinia chrysanthemi (recombinant)-rywn is 1.48 L/m2 (49%).EliminationThe geometric mean (%CV) apparent clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn is 0.31 L/hour/m2 (36%) and the apparent half-life is 18.2 hours (16%).MetabolismAsparaginase erwinia chrysanthemi (recombinant)-rywn is expected to be metabolized into small peptides by catabolic pathways. Specific PopulationsThere were no clinically significant differences in the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn based on age (1 to 52 years), weight (9 to 131 kg), or sex after the dose was adjusted by body surface area (BSA). The effect of renal and hepatic impairment on the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn has not been studied.Body Surface AreaThe apparent volume of distribution and apparent clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn increase with increasing BSA (0.44 to 2.53 m2). Race and EthnicityBlack (n=10) and Asian (n=5) patients had 29% lower clearance which may increase SAA exposure compared to White (n=61) patients. There were no clinically significant differences in clearance between Hispanic (n=28) and Non-Hispanic (n=53) patients.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The efficacy of RYLAZE for the treatment of patients with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who have developed hypersensitivity to E. coli-derived asparaginase as component of multi-agent chemotherapeutic regimen was evaluated in Study JZP458-201 (NCT04145531), an open-label, multi-cohort, multicenter trial. treatment course consisted of RYLAZE at various dosages administered intramuscularly every Monday, Wednesday, and Friday for total of doses to replace each dose of pegaspargase.For the 102 patients treated, the median age was 10 years (range, - 24 years); 57% were male and 43% were female; 73% were white, 12% were Black/African American, 5% were Asian, and 10% were of other or unknown race. Ninety-seven (94%) patients had experienced hypersensitivity reaction to pegaspargase, and patients (7%) had reported silent inactivation.The determination of efficacy was based on demonstration of the achievement and maintenance of nadir serum asparaginase activity (NSAA) above the level of 0.1 U/mL. The results of modeling and simulations showed that for dosage of 25 mg/m2 administered intramuscularly every 48 hours, the proportion of patients maintaining NSAA >= 0.1 U/mL at 48 hours after dose of RYLAZE was 93.6% (95% CI: 92.6%, 94.6%) [see Clinical Pharmacology (12.3)].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS RYLAZE is contraindicated in patients with history of:oSerious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis [see Warnings and Precautions (5.1)];oSerious pancreatitis during previous asparaginase therapy [see Warnings and Precautions (5.2)];oSerious thrombosis during previous asparaginase therapy [see Warnings and Precautions (5.3)];oSerious hemorrhagic events during previous asparaginase therapy [see Warnings and Precautions (5.4)].. oSerious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis [see Warnings and Precautions (5.1)];. oSerious pancreatitis during previous asparaginase therapy [see Warnings and Precautions (5.2)];. oSerious thrombosis during previous asparaginase therapy [see Warnings and Precautions (5.3)];. oSerious hemorrhagic events during previous asparaginase therapy [see Warnings and Precautions (5.4)].. RYLAZE is contraindicated in patients with history of:oSerious hypersensitivity reactions to RYLAZE, including anaphylaxis. (4)oSerious pancreatitis during previous L-asparaginase therapy. (4)oSerious thrombosis during previous L-asparaginase therapy. (4)oSerious hemorrhagic events during previous L-asparaginase therapy. (4). oSerious hypersensitivity reactions to RYLAZE, including anaphylaxis. (4). oSerious pancreatitis during previous L-asparaginase therapy. (4). oSerious thrombosis during previous L-asparaginase therapy. (4). oSerious hemorrhagic events during previous L-asparaginase therapy. (4).

DESCRIPTION SECTION.

11 DESCRIPTION Asparaginase erwinia chrysanthemi (recombinant)-rywn contains an asparagine specific bacterial enzyme (L-asparaginase). L-asparaginase is tetrameric enzyme that consists of four identical 35 kDa subunits with combined molecular weight of 140 kDa. The amino acid sequence is identical to native asparaginase Erwinia chrysanthemi (also known as crisantaspase). The activity of asparaginase erwinia chrysanthemi (recombinant)-rywn is expressed in units, defined as the amount of enzyme that catalyzes the conversion of 1umol of L-asparagine per reaction minute, per mg of protein.Asparaginase erwinia chrysanthemi (recombinant)-rywn is produced by fermentation of genetically engineered Pseudomonas fluorescens bacterium containing the DNA which encodes for asparaginase Erwinia chrysanthemi.RYLAZE (asparaginase erwinia chrysanthemi (recombinant)-rywn) injection is supplied as sterile, clear to opalescent, colorless to slightly yellow, preservative-free solution for intramuscular injection. Each 0.5 mL contains 10 mg asparaginase erwinia chrysanthemi (recombinant)-rywn and the inactive ingredients: polysorbate 80 (0.1 mg), sodium chloride (1.5 mg), sodium phosphate dibasic anhydrous (0.8 mg), sodium phosphate monobasic monohydrate (0.6 mg), and trehalose (32.1 mg). Sodium hydroxide may be added to adjust the pH. The pH is approximately 7.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION When replacing long-acting asparaginase product, the recommended dosage of RYLAZE is 25 mg/m2 administered intramuscularly every 48 hours. (2.1). 2.1 Recommended Dosage When replacing long-acting asparaginase product, the recommended dosage of RYLAZE is 25 mg/m2 administered intramuscularly every 48 hours.See the full prescribing information for the long-acting asparaginase product to determine the duration of administration of RYLAZE as replacement therapy.. 2.2 Recommended Monitoring and Dosage Modifications for Adverse Reactions Monitor patients bilirubin, transaminases, glucose, and clinical examinations prior to treatment every 2-3 weeks and as indicated clinically. If results are abnormal, monitor patients until recovery from the cycle of therapy. If an adverse reaction occurs, modify treatment according to Table 1.Table 1: Dosage ModificationsAdverse ReactionSeverityActionHypersensitivity Reaction [see Warnings and Precautions (5.1)] Grade 2oTreat the symptoms.Grade to 4oDiscontinue RYLAZE permanently.Pancreatitis [see Warnings and Precautions (5.2)] Grade to 4oHold RYLAZE for elevations in lipase or amylase 2 times the ULN, or for symptomatic pancreatitis.oResume treatment when lipase and amylase are 1.5 times the ULN and symptoms are resolved.oDiscontinue RYLAZE permanently if clinical necrotizing or hemorrhagic pancreatitis is confirmed.Thrombosis [see Warnings and Precautions (5.3)] Uncomplicated thrombosisoHold RYLAZE.oTreat with appropriate antithrombotic therapy.oUpon resolution of symptoms, consider resuming RYLAZE, while continuing antithrombotic therapy.Severe or life-threatening thrombosisoDiscontinue RYLAZE permanently.oTreat with appropriate antithrombotic therapy.Hemorrhage [see Warnings and Precautions (5.4)] Grade to 4oHold RYLAZE.oEvaluate for coagulopathy and consider clotting factor replacement as needed.oResume RYLAZE with the next scheduled dose if bleeding is controlled.Hepatotoxicity [see Warnings and Precautions (5.5)] Total bilirubin 3 times to <= 10 times the ULNoHold RYLAZE until total bilirubin levels decrease to <= 1.5 times the ULN.Total bilirubin 10 times the ULNoDiscontinue RYLAZE and do not make up missed doses. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.. oTreat the symptoms.. oDiscontinue RYLAZE permanently.. oHold RYLAZE for elevations in lipase or amylase 2 times the ULN, or for symptomatic pancreatitis.. oResume treatment when lipase and amylase are 1.5 times the ULN and symptoms are resolved.. oDiscontinue RYLAZE permanently if clinical necrotizing or hemorrhagic pancreatitis is confirmed.. oHold RYLAZE.. oTreat with appropriate antithrombotic therapy.. oUpon resolution of symptoms, consider resuming RYLAZE, while continuing antithrombotic therapy.. oDiscontinue RYLAZE permanently.. oTreat with appropriate antithrombotic therapy.. oHold RYLAZE.. oEvaluate for coagulopathy and consider clotting factor replacement as needed.. oResume RYLAZE with the next scheduled dose if bleeding is controlled.. oHold RYLAZE until total bilirubin levels decrease to <= 1.5 times the ULN.. oDiscontinue RYLAZE and do not make up missed doses.. 2.3 Preparation and Administration Instructions Ensure that medical support is available to appropriately manage anaphylactic reactions when administering RYLAZE [see Warnings and Precautions (5.1)].Visually inspect parenteral drug products for particulate matter, cloudiness, or discoloration prior to administration. If any of these are present, discard the vial. RYLAZE does not contain preservative.Use aseptic technique.oDetermine the dose, total volume of RYLAZE solution required, and the number of RYLAZE vials needed. More than one vial may be needed for full dose.oWithdraw the indicated injection volume of RYLAZE into the syringe for injection.oDo not shake the vial.oLimit the volume of RYLAZE at single injection site to mL.oIf the volume to be administered is greater than mL, divide the doses equally into multiple syringes, one for each injection site.oDiscard the remaining unused RYLAZE in the single-dose vial.oAdminister RYLAZE by intramuscular injection within hours after drawing the dose into the syringe(s).oRotate injection sites.oDo not inject RYLAZE into scar tissue or areas that are reddened, inflamed, or swollen.oIf needed, store the syringe(s) at room temperature (15C to 25C [59F to 77F]) or refrigerated at 2C to 8C (36F to 46F) for up to hours. The syringe does not need to be protected from light during storage.. oDetermine the dose, total volume of RYLAZE solution required, and the number of RYLAZE vials needed. More than one vial may be needed for full dose.. oWithdraw the indicated injection volume of RYLAZE into the syringe for injection.oDo not shake the vial.oLimit the volume of RYLAZE at single injection site to mL.oIf the volume to be administered is greater than mL, divide the doses equally into multiple syringes, one for each injection site.oDiscard the remaining unused RYLAZE in the single-dose vial.. oDo not shake the vial.. oLimit the volume of RYLAZE at single injection site to mL.. oIf the volume to be administered is greater than mL, divide the doses equally into multiple syringes, one for each injection site.. oDiscard the remaining unused RYLAZE in the single-dose vial.. oAdminister RYLAZE by intramuscular injection within hours after drawing the dose into the syringe(s).oRotate injection sites.oDo not inject RYLAZE into scar tissue or areas that are reddened, inflamed, or swollen.oIf needed, store the syringe(s) at room temperature (15C to 25C [59F to 77F]) or refrigerated at 2C to 8C (36F to 46F) for up to hours. The syringe does not need to be protected from light during storage.. oRotate injection sites.. oDo not inject RYLAZE into scar tissue or areas that are reddened, inflamed, or swollen.. oIf needed, store the syringe(s) at room temperature (15C to 25C [59F to 77F]) or refrigerated at 2C to 8C (36F to 46F) for up to hours. The syringe does not need to be protected from light during storage.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION oHypersensitivity Inform patients of the risk of allergic reactions, including anaphylaxis. Instruct the patient on the symptoms of allergic reactions and to seek medical advice immediately if they experience such symptoms [see Warnings and Precautions (5.1)].oPancreatitis Instruct patients on signs and symptoms of pancreatitis and to seek medical attention if they experience severe abdominal pain [see Warnings and Precautions (5.2)].oThrombosis Instruct patients on the risk of thrombosis and to seek medical advice immediately if they experience headache, arm or leg swelling, shortness of breath, and chest pain [see Warnings and Precautions (5.3)].oHemorrhage Advise patients to report any unusual bleeding or bruising to their healthcare provider [see Warnings and Precautions (5.4)].oHepatotoxicity Advise patients to report any jaundice, severe nausea or vomiting, or easy bleeding or bruising to their healthcare provider [see Warnings and Precautions (5.5)].oPregnancy Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with RYLAZE and for months after the last dose [see Use in Specific Populations (8.3)].oLactation Advise women not to breastfeed during treatment with RYLAZE and for week after the last dose [see Use in Specific Populations (8.2)].Manufactured by: Jazz Pharmaceuticals Ireland LimitedLeinster, IrelandU.S. License No. 2167 Distributed by:Jazz Pharmaceuticals, Inc.3170 Porter Drive, Palo Alto, CA 94304 Protected by U.S. Patent nos. 8,288,127 and 10,787,671RYLAZE(TM) is trademark of Jazz Pharmaceuticals plc or its subsidiaries.(C)2021 Jazz Pharmaceuticals. oHypersensitivity. Inform patients of the risk of allergic reactions, including anaphylaxis. Instruct the patient on the symptoms of allergic reactions and to seek medical advice immediately if they experience such symptoms [see Warnings and Precautions (5.1)].. oPancreatitis. Instruct patients on signs and symptoms of pancreatitis and to seek medical attention if they experience severe abdominal pain [see Warnings and Precautions (5.2)].. oThrombosis. Instruct patients on the risk of thrombosis and to seek medical advice immediately if they experience headache, arm or leg swelling, shortness of breath, and chest pain [see Warnings and Precautions (5.3)].. oHemorrhage. Advise patients to report any unusual bleeding or bruising to their healthcare provider [see Warnings and Precautions (5.4)].. oHepatotoxicity. Advise patients to report any jaundice, severe nausea or vomiting, or easy bleeding or bruising to their healthcare provider [see Warnings and Precautions (5.5)].. oPregnancy. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations (8.1)].. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with RYLAZE and for months after the last dose [see Use in Specific Populations (8.3)].. oLactation. Advise women not to breastfeed during treatment with RYLAZE and for week after the last dose [see Use in Specific Populations (8.2)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics The pharmacokinetic parameters of asparaginase erwinia chrysanthemi (recombinant)-rywn are presented based on serum asparaginase activity (SAA) following administration of the approved recommended dosage in pediatric and young adult patients (1 to 24 years), unless otherwise specified. The exposures for asparaginase erwinia chrysanthemi (recombinant)-rywn are summarized in Table 3. Asparaginase erwinia chrysanthemi (recombinant)-rywn maximum SAA (Cmax) and area under the SAA-time curve (AUC) increase proportionally over dosage range from 12.5 to 50 mg/m2 (0.5 to times the approved recommended dose of 25 mg/m2).Table 3: RYLAZE Pharmacokinetic Parameters Based on SAAParameterDose in CourseGeometric Mean (%CV)Cmax (U/mL)11.80 (40%)72.24 (42%)C48h (U/mL)10.33 (88%)70.40 (93%)AUC0-48h (h.U/mL)137.9 (39%)748.5 (41%)a SAA 48 hours after the most recent dose AbsorptionThe median tmax of asparaginase erwinia chrysanthemi (recombinant)-rywn is 10 hours. The mean absolute bioavailability for IM administration is 37% in healthy subjects.DistributionThe geometric mean (%CV) apparent volume of distribution of asparaginase erwinia chrysanthemi (recombinant)-rywn is 1.48 L/m2 (49%).EliminationThe geometric mean (%CV) apparent clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn is 0.31 L/hour/m2 (36%) and the apparent half-life is 18.2 hours (16%).MetabolismAsparaginase erwinia chrysanthemi (recombinant)-rywn is expected to be metabolized into small peptides by catabolic pathways. Specific PopulationsThere were no clinically significant differences in the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn based on age (1 to 52 years), weight (9 to 131 kg), or sex after the dose was adjusted by body surface area (BSA). The effect of renal and hepatic impairment on the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn has not been studied.Body Surface AreaThe apparent volume of distribution and apparent clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn increase with increasing BSA (0.44 to 2.53 m2). Race and EthnicityBlack (n=10) and Asian (n=5) patients had 29% lower clearance which may increase SAA exposure compared to White (n=61) patients. There were no clinically significant differences in clearance between Hispanic (n=28) and Non-Hispanic (n=53) patients.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryBased on findings from animal reproduction studies, RYLAZE can cause fetal harm when administered to pregnant woman. There are no available data on RYLAZE use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproductive and developmental toxicity studies, intramuscular administration of asparaginase Erwinia chrysanthemi to pregnant rats and rabbits during organogenesis resulted in structural abnormalities and embryo-fetal mortality (see Data) at exposures below those in patients at the recommended human dose. Advise pregnant women of the potential risk to fetus.In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and 15 to 20%, respectively.DataAnimal DataAnimal reproductive and developmental toxicity studies have not been conducted with RYLAZE.In embryofetal development studies, asparaginase Erwinia chrysanthemi was administered intramuscularly every other day during the period of organogenesis to pregnant rats (at 3, 6, or 12 mg/m2) and rabbits (at 0.12, 0.30, or 0.48 mg/m2). In rats given 12 mg/m2 (approximately 0.48 times the maximum recommended human dose), maternal toxicity of decreased body weight gain was observed, as was fetal finding of increased incidence of partially undescended thymic tissue. In rabbits, maternal toxicity consisting of decreased body weight was observed at 0.48 mg/m2 (approximately 0.02 times the maximum recommended human dose). Increased post-implantation loss, decrease in the number of live fetuses, and gross abnormalities (e.g., absent kidney, absent accessory lung lobe, additional subclavian artery, and delayed ossification) were observed at doses of >= 0.12 mg/m2 (approximately 0.005 times the maximum recommended human dose).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oLactation: Advise not to breastfeed. (8.2). oLactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy Risk SummaryBased on findings from animal reproduction studies, RYLAZE can cause fetal harm when administered to pregnant woman. There are no available data on RYLAZE use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproductive and developmental toxicity studies, intramuscular administration of asparaginase Erwinia chrysanthemi to pregnant rats and rabbits during organogenesis resulted in structural abnormalities and embryo-fetal mortality (see Data) at exposures below those in patients at the recommended human dose. Advise pregnant women of the potential risk to fetus.In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and 15 to 20%, respectively.DataAnimal DataAnimal reproductive and developmental toxicity studies have not been conducted with RYLAZE.In embryofetal development studies, asparaginase Erwinia chrysanthemi was administered intramuscularly every other day during the period of organogenesis to pregnant rats (at 3, 6, or 12 mg/m2) and rabbits (at 0.12, 0.30, or 0.48 mg/m2). In rats given 12 mg/m2 (approximately 0.48 times the maximum recommended human dose), maternal toxicity of decreased body weight gain was observed, as was fetal finding of increased incidence of partially undescended thymic tissue. In rabbits, maternal toxicity consisting of decreased body weight was observed at 0.48 mg/m2 (approximately 0.02 times the maximum recommended human dose). Increased post-implantation loss, decrease in the number of live fetuses, and gross abnormalities (e.g., absent kidney, absent accessory lung lobe, additional subclavian artery, and delayed ossification) were observed at doses of >= 0.12 mg/m2 (approximately 0.005 times the maximum recommended human dose).. 8.2 Lactation Risk SummaryThere are no data on the presence of asparaginase erwinia chrysanthemi (recombinant)-rywn in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with RYLAZE and for week after the last dose.. 8.3 Females and Males of Reproductive Potential RYLAZE can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingPregnancy testing is recommended in females of reproductive potential prior to initiating RYLAZE.ContraceptionAdvise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with RYLAZE and for months after the last dose.. 8.4 Pediatric Use The safety and effectiveness of RYLAZE in the treatment of ALL and LBL have been established in pediatric patients month to 17 years who have developed hypersensitivity to long-acting E. coli-derived asparaginase. Use of RYLAZE in these age groups is supported by evidence from an adequate and well-controlled study in adults and pediatric patients. The trial included 84 pediatric patients, including infants (1 month to 2 years), 62 children (2 years to 12 years old), and 20 adolescents (12 years to 17 years old). There were no clinically meaningful differences in safety or nadir serum asparaginase activity across age groups. The safety and effectiveness of RYLAZE have not been established in pediatric patients younger than month of age.. 8.5 Geriatric Use Clinical studies of RYLAZE did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHypersensitivity: Monitor for signs or symptoms. Discontinue RYLAZE for serious reaction. (5.1)oPancreatitis: Monitor for symptoms. Discontinue if pancreatitis occurs. (5.2)oThrombosis: Discontinue RYLAZE for severe or life-threatening thrombosis. Provide anticoagulation therapy as indicated. (5.3)oHemorrhage: Discontinue RYLAZE for severe or life-threatening hemorrhage. (5.4)oHepatotoxicity: Discontinue RYLAZE for grade increases of bilirubin. (5.5). oHypersensitivity: Monitor for signs or symptoms. Discontinue RYLAZE for serious reaction. (5.1). oPancreatitis: Monitor for symptoms. Discontinue if pancreatitis occurs. (5.2). oThrombosis: Discontinue RYLAZE for severe or life-threatening thrombosis. Provide anticoagulation therapy as indicated. (5.3). oHemorrhage: Discontinue RYLAZE for severe or life-threatening hemorrhage. (5.4). oHepatotoxicity: Discontinue RYLAZE for grade increases of bilirubin. (5.5). 5.1 Hypersensitivity Reactions Hypersensitivity reactions after the use of RYLAZE occurred in 25% of patients in clinical trials, and it was severe in 2% of patients [see Adverse Reactions (6.1)]. The median time from the first dose of RYLAZE to the onset of the first hypersensitivity event was 27 days (range 1-171 days). The most commonly observed reaction was rash (17%), and no patient experienced severe rash. The median time from the first dose to the first onset of rash was 33.5 days (range 1-127 days). Hypersensitivity reactions observed with L-asparaginase class products include angioedema, urticaria, lip swelling, eye swelling, rash or erythema, blood pressure decreased, bronchospasm, dyspnea, and pruritus.Because of the risk of serious allergic reactions (e.g., life-threatening anaphylaxis), administer RYLAZE in setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, oxygen, intravenous steroids, antihistamines) [see Dosage and Administration (2.3)]. Discontinue RYLAZE in patients with serious hypersensitivity reactions.. 5.2 Pancreatitis Pancreatitis was reported in 14% of patients in clinical trials of RYLAZE and was severe in 6% [see Adverse Reactions (6.1)]. Clinical pancreatitis occurred in 5% of patients, and it was severe in 4% of patients. Elevated amylase or lipase without clinical diagnosis of pancreatitis was observed in 9% of patients, and it was severe in 2% of patients treated with RYLAZE. Hemorrhagic or necrotizing pancreatitis have been reported with L-asparaginase class products.Inform patients of the signs and symptoms of pancreatitis, which, if left untreated, could be fatal. Evaluate patients with symptoms compatible with pancreatitis to establish diagnosis. Assess serum amylase and lipase levels in patients with any signs or symptoms of pancreatitis. Discontinue RYLAZE in patients with severe or hemorrhagic pancreatitis. In the case of mild pancreatitis, withhold RYLAZE until the signs and symptoms subside and amylase and/or lipase levels return to 1.5 times the ULN [see Dosage and Administration (2.2)]. After resolution of mild pancreatitis, treatment with RYLAZE may be resumed.. 5.3 Thrombosis Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been reported following treatment with L-asparaginase class products. Discontinue RYLAZE for thrombotic event, and administer appropriate antithrombotic therapy. Consider resumption of treatment with RYLAZE only if the patient had an uncomplicated thrombosis [see Dosage and Administration (2.2)].. 5.4 Hemorrhage Bleeding was reported in 17% of patients treated with RYLAZE, and it was severe in 1%. Most commonly observed reactions were bruising (8%) (contusion, increased tendency to bruise and injection site bruising) and nose bleeding (6%), which was severe in 1% of patients. Other observed bleeding reactions included hematuria (2%), disseminated intravascular coagulopathy (1%), rectal bleeding (1%) and gingival bleeding (1%) [see Adverse Reactions (6.1)].In patients treated with L-asparaginase class products, hemorrhage may be associated with increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia. Consider appropriate replacement therapy in patients with severe or symptomatic coagulopathy [see Dosage and Administration (2.2)].. 5.5 Hepatotoxicity Elevated bilirubin and/or transaminases occurred in 62% of patients treated with RYLAZE in clinical trials, and 12% had Grade >= elevations [see Adverse Reactions (6.1)].Inform patients of the signs and symptoms of hepatotoxicity. Evaluate bilirubin and transaminases prior to treatment every 2-3 weeks and as indicated clinically during treatment with RYLAZE. In the event of serious liver toxicity, discontinue treatment with RYLAZE and provide supportive care [see Dosage and Administration (2.2)].